WO2023104111A1 - Composés hétérocycliques condensés utilisés en tant qu'inhibiteurs de pi3kalpha - Google Patents

Composés hétérocycliques condensés utilisés en tant qu'inhibiteurs de pi3kalpha Download PDF

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WO2023104111A1
WO2023104111A1 PCT/CN2022/137307 CN2022137307W WO2023104111A1 WO 2023104111 A1 WO2023104111 A1 WO 2023104111A1 CN 2022137307 W CN2022137307 W CN 2022137307W WO 2023104111 A1 WO2023104111 A1 WO 2023104111A1
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alkyl
oxo
amino
methyl
chromen
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Xiaolin Hao
Yonghua LEI
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Nanjing Zenshine Pharmaceuticals Co., Ltd.
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention pertains to fused heterocyclic compounds that inhibit the mutated phosphoinositide 3-kinase ⁇ (PI3K ⁇ ) and are useful for the treatment of diseases and conditions such as cancer mediated by PI3K ⁇ mutations.
  • PI3K ⁇ mutated phosphoinositide 3-kinase ⁇
  • Protein kinases are enzymes crucial for multiple fundamental biological processes and complex functions such as regulation of the cell cycle and signal transduction.
  • the phosphoinositide 3-kinase (PI3K) is the family member of intracellular signal transducer enzymes that catalyze the phosphorylation of the 3-position hydroxyl group of the inositol ring of phosphatidylinositols.
  • PI3K signaling is involved in many disease states including cancer and inflammatory diseases such as allergic contact dermatitis and rheumatoid arthritis et, al., which makes PI3Ks become important therapeutic targets in recent decades.
  • PI3Ks are divided into three classes: class I, II, and III. Class I PI3Ks are further classified into four isoforms: PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ (Fruman, et, al., Phosphoinositide kinases. Anu. Rev. Biochem. 1998, 67, 481-507) .
  • the class I PI3Ks are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the pathways of Akt/PDK1, mTOR, the Tec family kinases, and the Rho family GTPases.
  • the PI3K isoforms have been implicated in a variety of human cancers and disorders and become as one of the most highly mutated systems in human cancers. Mutations in the gene coding for a PI3K isoform are point mutations clustered within several hotspots in helical and kinase domains. Because of the high rate of PI3K mutations, targeting of the mutations in this pathway may provide valuable therapeutic opportunities.
  • PI3K ⁇ isoform is of particular pharmacological target of interest since the over-activation of PI3K ⁇ signaling is one of the most frequent events leading to cancer.
  • Deregulation of the PI3K ⁇ pathway may occur by several different mechanisms, including somatic mutations and amplification of genes encoding key components of the PI3K ⁇ pathway (Courtney, K.D. et, al., The PI3K pathway as drug target in human cancer. J. Clin. Oncol. 2010, 28, 1075-1083. ) .
  • mutations in the gene coding for PI3K ⁇ or mutations which lead to upregulation of PI3K ⁇ are believed to occur within several hotspots in helical and kinase domains, such as E542K, E545K and H1047R, of which H1047R substitution in the kinase domain close to the C terminus and a cluster of three charge-reversal mutations (E542K, E545K, Q546K) in the helical domain of p110 ⁇ counts for 80%.
  • PIK3CA is mutated in 27%of breast cancer cases, 24%in endometrial cancer and 15%in colon cancer (Liu, P. et, al., Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discovery. 2009, 8, 627-644. ) . Due to its key role in regulating organismal glucose homeostasis, inhibition by pan PI3K inhibitors or PI3K ⁇ inhibitors which are potent against both mutant PI3K ⁇ and wild-type PI3K ⁇ often causes hyperglycemia and/or hyperinsulinemia (Busaidy NL, et al, Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway.
  • Hyperglycemia may be worsened or prolonged in insulin resistance patients and therefor results discontinuation of PI3K inhibitor treatment (Hopkins, B, et al, Suppression of insulin feedback enhances the efficacy of PI3K inhibitors, Nature, 2018, 560, 499-503) .
  • Enhancing selectivity for mutant PI3K ⁇ over wild-type PI3K ⁇ can potentially provide an increased window for complete inhibition of the pathologic signaling of mutant PI3K ⁇ in the cancer cells while limiting toxicities caused by affecting the wild-type PI3K ⁇ in the host tissues that control systemic metabolism (Okkenhaug K, et, al., Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov. 2016 Oct; 6 (10) : 1090-1105) .
  • PI3K ⁇ inhibitors currently are nearly equipotent to wild-type and mutant PI3K ⁇ .
  • the development of allosteric inhibitors targeting binding pocket near a known mutation may provide a route to selective PI3K ⁇ inhibition.
  • Allosteric inhibitors have a number of potential benefits over the canonical ATP competitive inhibitors, such as greater selectivity due to the less conserved binding site.
  • the present disclosure provides a new class of kinase inhibitors to PI3K ⁇ mutations.
  • the objective of the present invention is to provide a compound of formula (VI) , a stereoisomer thereof, or a pharmaceutically acceptable salt, solvates and prodrugs thereof:
  • L 1 is selected from -O- (CHR 1 ) p -, -N (R 11 ) - (CHR 1 ) p -;
  • R 1 is identical or different and each is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halogen, hydroxy, cyano;
  • R 11 is identical or different and each is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
  • R a is independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halogen, amino, nitro, hydroxy, cyano, -C (O) N (R aa ) 2 , C 3 -C 8 cycloalkyl, 4 to 7 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 4 to 7 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl are each optionally further substituted by one or more deuterium, C 1 -C 6 alkyl, halogen, hydroxy, amino, nitro, cyano, ester group, C 1 -C 6 alkoxy
  • Ring B is independently selected from
  • L 2 is CR 2 R 2 ’ ;
  • Each R 2 and R 2 ’ is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl or C 1 -C 6 haloalkyl;
  • Ring B is independently selected from:
  • Each R b is identical or different and each is independently selected from the group consisting of hydrogen, oxo, halogen, hydroxy, amino, nitro, cyano, ester group, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl and 4 to 7 membered heterocyclyl, wherein the C 1 -C 6 alky, C 3 -C 8 cycloalkyl and 4 to 7 membered heterocyclyl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, amino, nitro, cyano, ester group, carboxyl, alkoxy, hydroxyalkyl;
  • R c is identical or different and is each independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -S (O) 2 -alkyl, halogen, amino, nitro, hydroxy, cyano, C 3 -C 8 cycloalkyl and 4 to 7 membered heterocyclyl, wherein the C 3 -C 8 cycloalkyl and 4 to 7 membered heterocyclyl are each optionally further substituted by one or more deuterium, alkyl, halogen, hydroxy, amino, nitro, cyano, ester group, alkoxy;
  • n is an integer of 0, 1, 2, 3, 4 or 5;
  • p is an integer of 0, 1 or 2.
  • each L 1 is -N (R 11 ) - (CHR 1 ) p - (such as -NH-, ) .
  • each R a is independently selected from halogen, C 1 -C 6 alkyl (such as methyl, ethyl, propyl and isopropyl) , C 3 -C 8 cycloalkyl (such as cyclopropyl) , C 1 -C 6 alkoxy, hydroxy, cyano and
  • each R b is independently selected from hydrogen, halogen, oxo, C 1 -C 6 alkyl (such as methyl, ethyl, propyl and isopropyl) , cyclopropyl, carboxymethyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl substituted by one or more halogen (such as 2-fluoro-2-methylpropyl) and 4 to 7 membered heterocyclyl (such as oxetan-3-yl) .
  • halogen such as 2-fluoro-2-methylpropyl
  • heterocyclyl such as oxetan-3-yl
  • each R c is independently selected from hydrogen, C 1 -C 6 alkyl (such as methyl, ethyl, propyl and isopropyl) , C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, halogen, amino, nitro, hydroxy, cyano and -S (O) 2 -methyl.
  • Each Z 1 , Z 2 , Z 3 and Z 4 is independently selected from CH, N or CR c ;
  • R c is each independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -S (O) 2 -alkyl, halogen, amino, nitro, hydroxy, cyano;
  • L 1 is independently selected from -N (H) -, -N (C 1 -C 6 alkyl) -, -O-, -S-and -CH 2 -;
  • R a is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 3 -C 8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl;
  • R 1 is independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl and 5 or 6 membered heteroaryl;
  • L 2 is a bond
  • X 1 is a ring atom of ring B and ring B is connected to L 2 through X 1 atom, wherein X 1 is a carbon atom;
  • Ring B is independently selected from C 3 -C 8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl;
  • R 2 is identical or different and each is independently selected from hydrogen, deuterium, oxo, halogen, hydroxy, amino, nitro, cyano, ester group, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl, wherein C 3 -C 8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl are each optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, amino, nitro, cyano, ester group, carboxyl, C 1 -C 6 alkyl, deuterated C 1 -C 6 al
  • L 3 is independently selected from bond, -O-, - (CH 2 ) 1-4 -, -C (O) -, -C (O) N (H) -, -N (H) C (O) -, -C (O) N (C 1 -C 6 alkyl) -and -N (C 1 -C 6 alkyl) C (O) -, -S (O) 2 -, - (CH 2 ) 1-4 -C (O) -, -O- (CH 2 ) 1-4 -, -CH (C 1 -C 6 alkyl) -, C 3 -C 8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl.
  • R 3 is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -NH (C 1 -C 6 alkyl) , -N (C 1 -C 6 alkyl) 2 , C 3 -C 8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl, wherein C 3 -C 8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl are each optionally further substituted by one or more hydrogen, deuterium, oxo, halogen, hydroxy, amino, nitro, cyano, ester group, carboxyl, C 1 -C 6 al
  • R 31 is independently selected from hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -NH (C 1 -C 6 alkyl) and-N (C 1 -C 6 alkyl) 2 .
  • n is an integer of 0, 1, 2, 3, 4 or 5.
  • the stereoisomer or the pharmaceutically acceptable salt, solvates and prodrugs thereof each is independently selected from and
  • each R c is independently selected from hydrogen, halogen, hydroxy, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 alkoxy.
  • each R a is independently selected from hydrogen, halogen, hydroxy, cyano, C 1 -C 4 alkyl (such as methyl, ethyl) , C 1 -C 4 haloalkyl (such as trifluoromethyl) , C 1 -C 4 hydroxyalkyl (such as hydroxymethyl) , C 1 -C 4 alkoxy (such as methoxy) and C 3 -C 6 cycloalkyl (such as cyclopropyl) .
  • each R 1 is independently selected from hydrogen, halogen, hydroxy, cyano, C 1 -C 4 alkyl (such as methyl, ethyl) , deuterated C 1 -C 4 alkyl (such as methyl-d 3 ) , C 1 -C 4 haloalkyl (such as trifluoromethyl, difluoromethyl) and C 1 -C 4 alkoxy and C 3 -C 6 cycloalkyl (such as cyclopropyl) .
  • each L 2 is bond.
  • each ring B is independently selected from and
  • each R 2 is independently selected from hydrogen, halogen, oxo, cyano, C 1 -C 4 alkyl (such as methyl, ethyl, propyl and isopropyl) , C 1 -C 4 haloalkyl (such as trifluoromethyl, 2-fluoro-2-methylpropyl, 1, 1, 1-trifluoropropan-2-yl) , C 1 -C 4 hydroxyalkyl (such as2-hydroxy-2-methylpropyl) and C 3 -C 6 cycloalkyl (such as cyclopropyl) .
  • each L 3 is independently selected from bond, -O-, -CH 2 -, - (CH 2 ) 2 -, -C (O) -, -C (O) N (H) -, -C (O) N (C 1 -C 4 alkyl) 2 , -S (O) 2 -, -CH 2 -C (O) -, -CH (C 1 -C 4 alkyl) -, -O- (CH 2 ) 1-4 -
  • each R 3 is independently selected from hydrogen, -N (C 1 -C 6 alkyl) 2 ,
  • each R 3 is optionally further substituted by one or more hydrogen, deuterium, oxo, halogen, hydroxy, amino, nitro, cyano, ester group, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl and C 1 -C 6 alkoxy, -S (O) 2 R 31 and -C (O) R 31 .
  • the compound of formula (VII) is a compound of formula (VII-1) , a stereoisomer thereof, or a pharmaceutically acceptable salt, solvates and prodrugs thereof:
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 is independently selected from C, CR y and N;
  • R y is hydrogen or two R y and the atoms to which they are attached can form a 5 to 6 membered heterocycle or heteroaryl;
  • L 1 , L 3 , R a , R c , R 1 , R 2 , R 3 , Z 1 and m are defined as in formula (VII) .
  • the stereoisomer or the pharmaceutically acceptable salt, solvates and prodrugs thereof is selected from
  • G is selected from-C (O) R g , -C (O) OR g , -OC (O) R g , -C (O) N (R g ) 2 , -C (O) NH (O R g ) , -N (R g ) C (O) R g , -S (O) 2 R g , -S (O) 2 OR g , -OS (O) 2 R g , -S (O) 2 N (R g ) 2 , -N ( (R g ) S (O) 2 R g , -P (O) (R g ) 2 , -P (O) (OR g ) 2 , -OP (O) OR g , -B (OR g ) 2, -C (O) N (R g ) -S (O) 2 R g and -S (O) 2 N (R g ) -C (O
  • Each R g is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl, wherein C 3 -C 8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl are each optionally further substituted by one or more hydrogen, deuterium, oxo, halogen, hydroxy, amino, nitro, cyano, ester group, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl and C 1 -C 6 alkoxy.
  • Z 1 , Z 2 , Z 3 , Z 4 , L 1 , L 2 , L 3 , R a , R 1 , R 2 , R 3 , X 1 , Ring B and m are defined as in formula (VII) .
  • the preferred variables in the preferred embodiments of the compound of formula (VII) , the stereoisomer or the pharmaceutically acceptable salt, solvates and prodrugs thereof such as Z 1 , Z 2 , Z 3 , Z 4 , L 1 , L 2 , L 3 , R a , R 1 , R 2 , R 3 , X 1 , Ring B and m can be used for formula (VII-1) and formula (VIII) .
  • the compound of formula, (VI) , (VII) , (VII-1) or (VIII) the stereoisomer or the pharmaceutically acceptable salt, solvates and prodrugs thereof is selected from the table 1:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (VI) , (VII) , (VII-1) or (VIII) , the stereoisomer or a pharmaceutically acceptable salt, prodrug, or solvate salt thereof and one or more pharmaceutically acceptable carriers or excipients.
  • the compounds described herein may be used to treat diseases that are mediated by PI3K ⁇ mutations, or the compounds described herein may be used to prepare a medicament for treating diseases that are mediated by PI3K ⁇ mutations.
  • the disease is a hematologic malignancy.
  • the disease is lymphoma, such as Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) , follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma.
  • the disorder is multiple myeloma, or leukemia, such as acute lymphocytic leukemia (ALL) , acute myeloid leukemia (AML) , chronic lymphocytic leukemia (CLL) , small lymphocytic lymphoma (SLL) , myelodysplastic syndrome (MDS) , myeloproliferative disease (MPD) , chronic myeloid leukemia (CML) .
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • MDS myelodysplastic syndrome
  • MPD myeloproliferative disease
  • CML chronic myeloid leukemia
  • the disease is a solid tumor.
  • the indication is to treat solid tumor with PI3K ⁇ mutations, such as pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) , gastrointestinal cancer, prostate cancer, ovarian cancer, medulloblastoma, and breast cancer.
  • PDAC pancreatic ductal adenocarcinoma
  • HCC hepatocellular carcinoma
  • the compounds alone or with combination of other anti-cancer therapies may be used to treat prostate cancer, bladder cancer, colorectal cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, head and neck cancer, melanoma, neuroendocrine cancers, brain tumors, bone cancer, or soft tissue sarcoma.
  • a compound of Formula (VI) , (VII) , (VII-1) or (VIII) , the stereoisomer or a pharmaceutically acceptable salt, prodrug, or solvate may be used in combination with one or more additional therapeutic agents to treat cancers or inflammatory disorders.
  • the one or more additional therapeutic agents may be a chemotherapeutic agent, a radiotherapy, a targeted therapy, an immunotherapeutic agent or any current best of care treatment, either as a small molecule or a biologic nature.
  • methods of treating a PI3K ⁇ mutation disorder comprise administering to a subject in need thereof a compound of Formula (VI) , (VII) , (VII-1) or (VIII) , the stereoisomer or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical formulation thereof are provided.
  • one or more hydrogen atoms, carbon atoms or other atoms of the compound of Formula (VI) , (VII) , (VII-1) or (VIII) , the stereoisomer or a pharmaceutically acceptable salt, prodrug, or solvate salt thereof can be substituted by an isotope of a hydrogen atom, a carbon atom or other atoms, respectively.
  • the compound of Formula (VI) , (VII) , (VII-1) or (VIII) , the stereoisomer or a pharmaceutically acceptable salt, prodrug, or solvate salt thereof includes all radioactive labeled bodies thereof.
  • Such the "radioactive labeling" and “radioactive labeled form” of the compound of Formula (VI) , (VII) , (VII-1) or (VIII) , the stereoisomer or a pharmaceutically acceptable salt, prodrug, or solvate salt thereof are included in the present invention, respectively, and are useful as a study and/or diagnostic tool in metabolized drug dynamic state study and binding assay.
  • Examples of an isotope which can be incorporated into the compound of the compound of Formula (VI) , (VII) , (VII-1) or (VIII) , the stereoisomer or a pharmaceutically acceptable salt, prodrug, or solvate salt thereof of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom and a chlorine atom, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • a particularly preferable example of an isotope which can be incorporated into the compound of Formula (VI) , (VII) , (VII-1) or (VIII) , the stereoisomer or a pharmaceutically acceptable salt, prodrug, or solvate salt thereof of the present invention is 2 H (i.e., heavy hydrogen atom) , and can be prepared by the method shown in Reference examples of the present description, or the method well-known in the art.
  • a heavy hydrogen atom is expressed as "D" in Reference examples of the present description.
  • the compound of Formula (VI) , (VII) , (VII-1) or (VIII) , the stereoisomer or a pharmaceutically acceptable salt, prodrug, or solvate salt thereof of the present invention in which a hydrogen atom has been converted into a heavy hydrogen atom are excellent in respect of bioavailability, metabolism safety, drug efficacy, and toxicity as compared with unconverted forms, in some cases, and can be useful as medicaments.
  • n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • pyridine is an example of a 6-membered heteroaryl ring
  • thiophene is an example of a 5-membered heteroaryl ring.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group comprising 1 to 20 carbon atoms, preferably an alkyl having 1 to 8 carbon atoms, more preferably an alkyl having 1 to 6 carbon atoms (C 1 -C 6 alkyl) , and most preferably an alkyl having 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-di
  • C 1-4 alkyl means an alkyl group having 1 to 4 carbon atoms.
  • C 1-4 alkyl is intended to include C 1 alkyl (methyl) , C 2 alkyl (ethyl) , C 3 alkyl (n-propyl, isopropyl) , C 4 alkyl (i.e., n-butyl, t-butyl, isobutyl, sec-butyl) .
  • the alkyl group can be substituted or unsubstituted. When substituted, the substituent group (s) can be substituted at any available connection point.
  • the substituent group (s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and carboxylate group, and preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
  • the alkenyl group may be in “cis” or “trans” configurations, or altematively in “E” or "Z” configurations.
  • the alkenyl is preferably an alkenyl having 2 to 8 carbon atoms, more preferably an alkenyl having 2 to 6 carbon atoms (C 2 -C 6 alkenyl) , and most preferably an alkenyl having 2 to 3 carbon atoms.
  • the alkenyl can be further substituted by other related group, for example alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxy or carboxylate group.
  • other related group for example alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxy or carboxylate group.
  • alkynyl refers to an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C ⁇ C) having the number of carbon atoms designated.
  • the alkynyl is preferably an alkynyl having 2 to 8 carbon atoms, more preferably an alkynyl having 2 to 6 carbon atoms (C 2 -C 6 alkenyl) , and most preferably an alkynyl having 2 to 3 carbon atoms.
  • the alkynyl can be further substituted by other related group, for example alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxy or carboxylate group.
  • other related group for example alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxy or carboxylate group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group having 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms (i.e., (C 3-8 cycloalkyl means a cycloalkyl with three to eight carbon atoms) , and more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like.
  • Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring.
  • the cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • the cycloalkyl can be further substituted by other related group, for example alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxy or carboxylate group.
  • other related group for example alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxy or carboxylate group.
  • aryl refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic.
  • Particular C 6-10 aryl groups are those having from 6 to 10 annular (i.e., ring) carbon atoms (for example, phenyl and naphthyl) .
  • An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position.
  • an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
  • Non-limiting examples thereof include:
  • the aryl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxy and carboxylate group.
  • heteroaryl refers to an unsaturated aromatic cyclic group having annular (i.e., ring) carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, phosphorus, oxygen and sulfur.
  • a heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic.
  • the heteroatoms disclosed herein are selected from O, S and N.
  • a 5-to 10-membered heteroaryl is specifically intended to include any 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl group.
  • the heteroaryl is more preferably 5 or 6 membered heteroaryl, for example, imidazolyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; and more preferably triazolyl, pyrrolyl, thienyl, thiazolyl and pyrimidinyl.
  • Non-limiting examples thereof include:
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • the substituent group (s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxy and carboxylate group.
  • heterocyclyl refers to a 3 to 20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group, wherein one or more ring atoms are heteroatoms selected from the group consisting of N, O and S (O) m (wherein m is an integer of 0 to 2) , but excluding -O-O-, -O-S-or -S-S-in the ring, with the remaining ring atoms being carbon atoms.
  • the heterocyclyl has 3 to 12 ring atoms wherein 1 to 4 atoms are heteroatoms; more preferably, the heterocyclyl has 4 to 10 ring atoms; and most preferably 4 to 7 ring atoms.
  • the term “4-to 10-membered heterocyclyl” means the heterocyclyl having 4 to 10 ring atoms.
  • monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, and preferably tetrahydrofuranyl, and tetrahydropyranyl, pyrazolyl, morpholinyl, piperazinyl and pyranyl.
  • Polycyclic heterocyclyl includes a heterocyclyl having a spiro ring, fused ring or bridged ring.
  • the heterocyclyl having a spiro ring, fused ring or bridged ring is optionally bonded to another group via a single bond, or further bonded to other cycloalkyl, heterocyclyl, aryl and heteroaryl via any two or more atoms on the ring.
  • the heterocyclyl group can be optionally substituted or unsubstituted.
  • the substituent group (s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and carboxylate group.
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group substituted with one or more halogen that may be the same of different, wherein the alkyl is as defined above.
  • C 1-6 haloalkyl refers to a C 1-6 alkyl group wherein the alkyl group is substituted with one or more halogen atoms.
  • a C 1-6 haloalkyl may be selected from fluormethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, 1, 1-difluoroethyl.
  • alkoxy refers to an -O- (alkyl) or an -O- (unsubstituted cycloalkyl) group, wherein the alkyl is as defined above.
  • the alkoxy is preferably an alkoxy having 1 to 8 carbon atoms, more preferably an alkoxy having 1 to 6 carbon atoms (C 1 -C 6 alkoxy) , and most preferably an alkoxy having 1 to 3 carbon atoms.
  • Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group can be optionally substituted or unsubstituted.
  • the substituent group (s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxy and carboxylate group.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein the alkoxy is as defined above.
  • deuterium refers to an isotope of hydrogen that has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen, the symbol of deuterium is “D” .
  • deuterated alkyl refers to an alkoxy group substituted by one or more deuterium, wherein the alkyl is as defined above.
  • hydroxyalkyl refers to an alkoxy group substituted by one or more hydroxy, wherein the alkyl is as defined above.
  • alkylthio refers to “-S-alkyl” , wherein the alkyl is as defined above.
  • -C (O) NH-alkyl or “-NHC (O) -alkyl” refers to an “-C (O) NH-” group connected with an alkyl, wherein the alkyl is as defined above.
  • methylcarbamoyl refers to
  • ester group refers to an “-C (O) O -” group connected with an alkyl, wherein the alkyl is as defined above.
  • amino refers to a -NH 2 group.
  • -NH (C 1 -C 6 alkyl) or “-N (C 1 -C 6 alkyl) 2 ” refers to an amino substituted by one or two C 1 -C 6 alkyl.
  • nitro refers to a -NO 2 group.
  • hydroxy refers to an -OH group.
  • thiol refers to an -SH group.
  • cyano refers to a -CN group.
  • Optionally substituted means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties.
  • a "substituted" atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group (up to and including that every hydrogen atom on the designated atom or moiety is replaced with a selection from the indicated substituent group) , provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., -CH 3 ) is optionally substituted, then up to 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.
  • a salt or "a Pharmaceutically acceptable salt” means a salt prepared by conventional means, and are well known by those skilled in the art.
  • the “pharmacologically acceptable salts” include basic salts of inorganic and organic acids (Berge et al., J. Pharm. Sci. 1977, 66: 1) .
  • a " solvate” is formed by treating a compound in a solvent. Solvates of salts of the compounds are also provided. In the case of treating compounds with water, the solvate is hydrates.
  • a “prodrug” includes any compound that converts into a compound of the present invention, when administered to a subject, e.g., upon metabolic processing of the prodrug.
  • stereoisomer refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • treat or “treating” in reference to a disorder means to ameliorate or prevent the disorder or one or more of the biological manifestations of the disorder, to interfere with one or more points in the biological cascade that leads to or is responsible for the disorder, to alleviate one or more of the symptoms or effects associated with the disorder.
  • treatment includes prevention of the disorder, and “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a disorder or biological manifestation thereof, or to delay the onset of such disorder or biological manifestation thereof.
  • Subject refers to a human (including adults and children) or other animals.
  • patient refers to a human.
  • safe and effective dose in reference to a compound of formulas, or a pharmaceutically acceptable salt, prodrug, or solvate thereof an amount sufficient to treat the patient's condition but low enough to avoid serious side effects.
  • a safe and effective dose of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound) ; the route of administration chosen; the disorder being treated; the severity of the disorder being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors.
  • potencies of compounds as inhibitors of an enzyme activity can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results.
  • concentrations at which each compound inhibits the activity can be determined by the concentration that inhibits 50%or 90%of the activity in a biochemical assay, which can be accomplished using conventional techniques known in the art, including the techniques describes in the examples below.
  • the compounds of the present invention may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods are well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of representative compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.
  • the starting materials used in the examples of the present invention are known and commercially available, or can be synthesized by adopting or according to known methods in the art.
  • the structures of the compounds of the present invention were identified by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS) .
  • 1H-NMR spectra are recorded on a Bruker 400 MHZ NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet) , coupling constant (s) in Hertz (Hz) and number of protons.
  • solvent refers to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene ( “Tol” ) , acetonitrile, tetrahydrofuran ( “THF” ) , dimethylformamide ( “DMF” ) , ethyl acetate (EA or EtOAc) , dichloromethane (DCM) , diethyl ether, methanol, pyridine and the like.
  • the solvents used in the reactions of the present invention are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen and argon.
  • SFC refers to Supercritical Fluid Chromatography
  • the stereoisomers of example compounds can be prepared with chiral SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um) .
  • DIEA or “DIPEA” refers to N, N-Diisopropylethylamine.
  • Pd (dba) 2 refers to “Tris (dibenzylideneacetone) dipalladium”
  • X-phos refers to Chloro (2-dicyclohexylphosphino-2', 4', 6'-tri-i-propyl-1, 1'-biphenyl) (2'-amino-1, 1'-biphenyl-2-yl) palladium (II) .
  • TAA Trifluoroacetic acid
  • LHMDS refers to Lithium bis (trimethylsilyl) amide.
  • m-CPBA refers to m-ChloroperbenzoicAcid.
  • Pd (PPh 3 ) 4 refer to “Tetrakis (triphenylphosphine) palladium” .
  • Pd (dppf) 2 Cl 2 refers to [1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) .
  • STAB refers to “Sodium Triacetoxyborohydride” .
  • Tf 2 O refers to “Trifluoromethanesulfonic anhydride” .
  • EDC refers to “1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide” .
  • MTBE refers to “Methyl tert-butyl ether” .
  • Pd (PPh 3 ) 2 Cl 2 refers to “Bis (triphenylphosphine) palladium (II) chloride” .
  • NMP refers to “N-methylpyrrolidone” .
  • NBS N-Bromosuccinimide
  • HATU refers to “2- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate” .
  • CuTC refers to “thiophene-2-carbonyloxycopper” .
  • B (PIN) 2 refers to “Bis (pinacolato) diboron” .
  • Methyl 2- ( (1- (2- (ethylthio) -6-methyl-4-oxo-4H-chromen-8-yl) ethyl) amino) benzoate is prepared in accordance with the method in WO2021202964A1
  • Steps 2-7 used the methods as described for methyl 2- ( (1- (2- (ethylthio) -6-methyl-4-oxo-4H-chromen-8-yl) ethyl) amino) benzoate WO2021202964A1.
  • stereoisomers of example 20 were prepared with chiral SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um) and arbitrarily assigned
  • Examples 21-53 were prepared in a similar manner as the preparation of example 95, and their stereoisomers can be prepared with chiral SFC in a similar manner as the preparation of the stereoisomers of example 20.
  • Step 1 To a solution of methyl 4-bromo-2- (bromomethyl) benzoate (1 g, 3.25 mmol, 1 eq) , 2-met hoxyethanamine (732 mg, 9.74 mmol, 846.83 uL, 3 eq) in toluene (15 mL) was added TEA (985 mg, 9.74 mmol, 1.36 mL, 3 eq) . The mixture was stirred at 115°C for 12 hr. LCMSshowed desire d mass was detected The reaction mixture was added with water (30ml) , extracted with EtOAc (50 ml*3) to give the organic phase.
  • Step 2 A mixture of 5-bromo-2- (2-methoxyethyl) isoindolin-1-one (400 mg, 1.48 mmol, 1 eq) , 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (752 mg, 2.96 mmol, 2 eq) , KOAc (435 mg, 4.44 mmol, 3 eq) , Pd 2 (dba) 3 (135 mg, 148.08 ⁇ mol, 0.1 eq) and ditert-butyl- [2- (2, 4, 6-triisopropylphenyl) phenyl] phosphane (62 mg, 148.08 ⁇ mol, 0.1 eq) in dioxane (8 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N
  • the crude product was purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 um; mobile phase: [water (FA) -ACN] ; B%: 55%-85%, 7 min) to give 6-chloro-3- [1- (2-ethylsulfanyl -3, 6-dimethyl-4-oxo-chromen-8-yl) ethylamino] pyridine-2-carboxylic acid (290 mg, 669.87 ⁇ mol, 58.9%yield, 100%purity) as yellow solid.
  • 6-chloro-3- ( (1- (3, 6-dimethyl-2- (2-methyl-2H-indazol-5-yl) -4-oxo-4H-chromen-8-yl) ethyl) amino) picolinic acid is prepared in accordance with the method of Example 1.
  • 6-chloro-3- ( (1- (3, 6-dimethyl-2- (4-morpholinophenyl) -4-oxo-4H-chromen-8-yl) ethyl) amino) picolinic acid is prepared in accordance with the method of Example 76.
  • Step d To a solution of tert-butyl 2- [1- [6-methyl-2- (2-methylpyrazolo [3, 4-c] pyridin-5-yl) -4-oxo-chromen-8-yl] ethylamino] benzoate (20 mg, 39.17 ⁇ mol, 1 eq) in ACN (2 mL) was added HCl (12 M, 13.06 uL, 4 eq) . The mixture was stirred at 80 °C for 1 hr. LCMS showed desired mass was detected. The reaction mixture was concentrated under vacuum to give the residue.
  • 105A and 105B were assigned arbitrarily.

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Abstract

La présente invention concerne des antagonistes de l'enzyme. La présente invention concerne des composés ayant une structure représentée par la formule (VI), (VII), (VII-1) ou (VIII), le stéréoisomère ou les sels, solvates et promédicaments pharmaceutiquement acceptables de ceux-ci. L'invention concerne en outre des utilisations des composés de formule (VI), (VII), (VII-1) ou (VIII) dans le traitement de cancers.
PCT/CN2022/137307 2021-12-08 2022-12-07 Composés hétérocycliques condensés utilisés en tant qu'inhibiteurs de pi3kalpha WO2023104111A1 (fr)

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US11878970B2 (en) 2021-05-27 2024-01-23 Petra Pharma Corporation Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of disease
WO2024044769A1 (fr) * 2022-08-26 2024-02-29 Mirati Therapeutics, Inc. Pyridopyrimidinones substituées
WO2024097721A1 (fr) 2022-11-02 2024-05-10 Petra Pharma Corporation Ciblage de poches allostériques et orthostériques de phosphoinositide 3-kinase (pi3k) pour le traitement d'une maladie

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WO2022235574A1 (fr) * 2021-05-03 2022-11-10 Petra Pharma Corporation Inhibiteurs chroménone allostériques de la phosphoinositide 3-kinase (pi3k) pour le traitement de maladies
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WO2011051704A1 (fr) * 2009-10-27 2011-05-05 Astrazeneca Ab Dérivés de chroménone à activité antitumorale
WO2021202964A1 (fr) * 2020-04-03 2021-10-07 Petra Pharma Corporation Inhibiteurs chroménone allostériques de la phosphoinositide 3-kinase (pi3k) pour le traitement de maladies associées à la modulation de pi3k
WO2022235575A1 (fr) * 2021-05-03 2022-11-10 Petra Pharma Corporation Inhibiteurs chroménone allostériques de la phosphoinositide 3-kinase (pi3k) pour le traitement d'une maladie
WO2022235574A1 (fr) * 2021-05-03 2022-11-10 Petra Pharma Corporation Inhibiteurs chroménone allostériques de la phosphoinositide 3-kinase (pi3k) pour le traitement de maladies
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11873295B2 (en) 2021-05-03 2024-01-16 Petra Pharma Corporation Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of disease
US11878970B2 (en) 2021-05-27 2024-01-23 Petra Pharma Corporation Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of disease
WO2024008122A1 (fr) * 2022-07-07 2024-01-11 海创药业股份有限公司 Inhibiteur de pi3k, procédé de préparation associé et utilisation associée
WO2024044769A1 (fr) * 2022-08-26 2024-02-29 Mirati Therapeutics, Inc. Pyridopyrimidinones substituées
WO2024097721A1 (fr) 2022-11-02 2024-05-10 Petra Pharma Corporation Ciblage de poches allostériques et orthostériques de phosphoinositide 3-kinase (pi3k) pour le traitement d'une maladie

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